Effect of transcutaneous electrical nerve stimulation of acupoints on respiratory outcomes of COVID‐19 patients with moderate pulmonary involvement: A parallel randomized clinical trial

Abstract Background and aims Experiencing respiratory symptoms, especially dyspnea and decreased oxygen saturation (SpO2) level in patients with coronavirus disease 2019 (COVID‐19) is associated with increased mortality. The present study was conducted to investigate the effect of transcutaneous electrical nerve stimulation of acupoints (Acu‐TENS) on the respiratory outcomes of COVID‐19 patients with moderate pulmonary involvement. Methods In these three‐blind parallel randomized clinical trials, 84 patients with COVID‐19 admitted to a referral hospital were selected by the convenience sampling method. Participants were randomly assigned to Acu‐TENS (n = 42) and control (n = 42) groups. The Acu‐TENS group received Acu‐TENS over the EX‐B1 (Dingchuan) acupuncture point for 45 min for four consecutive days, while participants in the control group received no intervention. Participants' respiratory outcomes, including oxygen saturation, vital signs, and the severity of dyspnea, were evaluated before and after each intervention on four consecutive days. In addition, the need for mechanical ventilation on Days 4, 8, and 12 and the disease's outcome (death or survival) were recorded in SPSS software version 16, and finally, data were analyzed using an independent samples t‐test. Results SpO2, the number of patients without the need for mechanical ventilation, and patient survival after the intervention were significantly higher in the Acu‐TENS group compared with the control group (<0.001). However, respiratory rate, heart rate, and the severity of dyspnea after the intervention were not significantly different between the two groups (p > 0.05). Conclusion The use of Acu‐TENS could improve SpO2 as a respiratory outcome of patients with COVID‐19 with moderate pulmonary involvement and it can be used as a therapeutic intervention.


| INTRODUCTION
Patients with COVID-19 experience different symptoms. However, the main symptoms of COVID-19 are dyspnea and decreased oxygen saturation (SpO 2 ). Even patients may have silent hypoxemia despite the exacerbation of the infection. 1 According to the guideline provided by the Ministry of Health of Iran on the diagnosis and treatment of COVID-19, patients with symptoms such as dyspnea, chest pain, with or without fever ≥ 38, SpO 2 between 90% and 93%, and pulmonary involvement less than 50% are in the moderate respiratory phase. In the initial and mild phases of COVID-19, respiratory involvement is rarely seen. In addition, in the severe phase of the disease, despite the noninvasive oxygen therapy, the arterial oxygen saturation level is less than 88%, symptoms of respiratory failure occur, and shock and multiple organ failure can also occur. 2 According to an existing retrospective study, the onset of shortness of breath in these patients is usually 5-6 days after the symptoms. 3 But the occurrence of dyspnea and hypoxia in critically ill patients can occur after a week from the onset of the disease. 4 Nonetheless, its progression to acute respiratory distress syndrome is on average, 2.5 days after the onset of shortness of breath, in which case, it is necessary to admit to the intensive care unit (ICU) and use mechanical ventilation. 3 Therefore, control and management of respiratory signs and symptoms in patients with COVID-19 are among the most important therapeutic interventions; because dyspnea and low levels of SpO 2 increase the risk of death. 5 Various invasive and noninvasive treatments have been used to manage dyspnea in COVID-19 patients. One of the invasive methods is mechanical ventilation, while this method can have several complications for patients. 6 Several studies have used noninvasive interventions to reduce dyspnea in these patients, including prone position, 7 vague nerve stimulation, 8 electrical stimulation through the skull, 9 and inhalation combination oxygen/hydrogen. 10 One of the noninvasive methods is transcutaneous electrical nerve stimulation of acupoints (Acu-TENS), which may be a potentially effective treatment with the least side effects compared to other methods for relieving the various symptoms and complications of COVID-19 patients. 11 However, it must be acknowledged that this intervention is an invasive method and has several complications such as bleeding, pneumothorax, infection, vasovagal reaction, pain, and other complications that can occasionally be life-threatening. 12 However, electrical stimulation can be used instead of a needle to stimulate acupuncture points, which is the percutaneous electrical stimulation in acupuncture points or Acu-TENS. As one of the most modern methods based on acupuncture, this technique has been employed in several studies. 13 For example, in studies on the respiratory outcomes of patients with lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma, the effectiveness of this method has been reported in improving the respiratory symptoms and respiratory capacity of patients. [14][15][16][17][18] However, Öncü and Zincir found that applying Acu-TENS in patients with COPD in the acute exacerbation phase does not affect respiratory parameters. 19 It is noteworthy that respiratory diseases have different conditions, and there are possible differences in the effectiveness of the Acu-TENS method on the respiratory conditions of patients. Further, the incidence of respiratory involvement in COVID-19 patients is high.
Accordingly, the present study aimed to investigate the effect of Acu-TENS on respiratory outcomes in hospitalized COVID-19 patients with moderate pulmonary involvement.

| Study design
A parallel, two-armed, triple-blind clinical trial design was applied in this study. The independent variable in this research is Acu-TENS and the dependent variables are SpO 2 , respiratory rate, and heart rate, the severity of dyspnea, as the respiratory outcome of the disease.

| Participants
The participants of this study included patients with COVID-19 admitted to a hospital in an urban area (Shahroud) of Iran from June to September 2021.
The inclusion criteria for participating in the study were the confirmation of the diagnosis of COVID-19 based on the polymerase chain reaction or computerized tomography scan findings (Ground-glass opacities [GGO]) by a physician, moderate pulmonary involvement (SpO 2 between 90% and 93% and pulmonary involvement less than 50%) according to the guideline of the Ministry of Health of Iran, 2 and the age range of more than 18 and less than 70 years.
On the other hand, hospitalized patients with the other clinical manifestations of COVID-19 and no pulmonary involvement, use of bronchodilator before the intervention, history of respiratory disease, history of the therapeutic use of electricity, drug and alcohol abuse, and smoking addiction were some of the exclusion criteria. Moreover, patients suffering from comorbidities such as advanced cancer, liver failure, renal failure requiring dialysis, congestive heart failure, having a cardiac pacemaker and cardiac conduction disorders, as well as having a history of allergies, skin allergies, and skin lesions in the electrode area were excluded from the study. The other exclusion criteria included moderate to severe scoliosis, obesity (body mass index above 35), psychiatric disorders, brain vascular disorders, history of mechanical ventilation before the intervention, and inability to sit in a semi-sitting position for any reason.

| Sample size and sampling
The sample size was estimated to be 42 people in each group considering previous studies, based on the results of mechanical ventilation 20 and shortness of breath, 21 and considering the error of the first type of 0.05 and the power of 80%. Convenience sampling was applied to enroll eligible participants in the study. Then, eligible participants were randomly divided into Acu-TENS and control groups using the quadruple blocking method. Accordingly, after creating a random sequence using SPSS version 16 syntax, a nontransparent envelope with a wrapper was prepared for allocation concealment. 22 First, codes "A" and "B" were assigned to the Acu-TENS and control groups, respectively. Each of the randomly included sequences was recorded on the cards and placed inside the envelopes. The principal investigator registered eligible participants in the order of their arrival, and then each participant was asked to select one of the envelopes. Participants who chose A or B entered the Acu-TENS or control group, respectively ( Figure 1). ward. The patient's RR and HR were counted in one full minute. In addition, the patient's SpO 2 was checked using the portable pulse oximetry (made in Iran) linked to a reusable finger sensor probe (Calibration number Q995HE222) without supplemental oxygen on room air. The vital sign was assessed before and after the intervention for four consecutive days in COVID-19 patients.

| The visual analog scale for dyspnea (VASD)
The sensation of dyspnea is subjective, but its severity can be quantified using the visual analog scale. This scale is a simple tool for assessing patients' dyspnea, consisting of a 10-cm horizontal line rated from 0 to 10; a score of zero indicates no dyspnea, while a score of 10 represents the highest severity of dyspnea. Accordingly, scores 1-3, 4-7, and above 7 demonstrate mild, moderate, and severe dyspnea, respectively. 23 The severity of dyspnea was evaluated before and after intervention for four consecutive days in COVID-19 patients.

| Intervention
In the Acu-TENS group, a trained physiotherapist identified the acupuncture point EX-B1 (Located on both sides of the spinous process of the seventh cervical vertebra); this point has been used in various studies to manage respiratory symptoms. [14][15][16][17][18] Then, the physiotherapist connected two 5 × 5 cm plastic electrodes at the EX-B1 acupuncture point, and the electrodes were related to the NOVIN 701 P PLUS-STIMULATOR (Iranian manufacturer and serial number AX212088). Next, an electric current with a pulse of 200 microseconds and a frequency of 4 Hz Acu-TENS was applied at the point for 45 min 25 for four consecutive days.
The device was connected to the front of the chest (unreal treatment point/not related to breathing) for the control group by applying an extremely low-intensity electric current for 45 min for four consecutive days. It should be noted that the COVID-19 treatment protocol prescribed by the physician was almost the same in both groups, and all patients received the same treatment.
As mentioned, the intervention was implemented by a trained physiotherapist. One of the researchers collected the data using the mentioned tools without knowing the group of participants. The data collection tool related to each person was coded based on his hospital file number, and then the data was entered into the SPSS software by the researcher's colleague. Due to the accuracy of the collector in collecting and recording data in the tools, no data was missing. In addition to the participants, the data collector who assessed outcomes and the statistical data analyst were unaware of the allocation of the participants.

| Data analysis
The results were analyzed using SPSS software version 16. In the statistical tests, a significance level of p < 0.05 and a confidence interval (CI) of 95% was used as the p-value. The Shapiro-Wilk test and histogram plot were used to determine the normality of the data.
The data were summarized and analyzed using descriptive and inferential statistics (Chi-square tests, Fisher's exact test, and independent samples t-test, repeated-measures ANOVA).

| RESULTS
In the present study, 175 eligible participants with COVID-19 were included in the initial study list, of which 91 persons did not meet the inclusion criteria, and 26 people declined to participate in the study.
Finally, 84 participants were randomly allocated to two Acu-TENS (n = 42) and control (n = 42) groups. During the intervention days, two patients in the control group had attrition due to changes in the treatment protocol, and eventually, the data of 82 participants underwent analysis.

| Demographic characteristics and homogeneity comparisons
The mean (SD) of age in the Acu-TENS and control groups was 56.88  Table 1. There was no significant difference between the demographic characteristics of the Acu-TENS and control groups, and the two groups were homogeneous (p > 0.05).

| SpO 2 level
The mean and SD of SpO 2 levels before and after the intervention and differences in the SpO 2 level before and after the intervention for 4 days in two groups are provided in Table 2. Based on the comparison of the mean differences in SpO 2 levels in the first to fourth days before and after the intervention between the Acu-TENS and control groups, the intervention increased the arterial SpO 2 level in the Acu-TENS group (Table 2).
Repeated measurement analysis was performed on the level of SpO 2 (before, after, and the difference before and after). In all analyses, the Muchly test is significant, implying that the sphericity assumption is not satisfied; therefore, the Greenhouse-Geisser statistics were used to examine the effect of time, group, and timegroup interaction.
The results revealed that before the SpO 2 level, the effect of time was significant (p < 0.001), representing that there was a difference in the SpO 2 level before the intervention between 4 days.
Additionally, the time-group interaction was significant (p < 0.001) and indicated that before the intervention, the SpO 2 level had no similar changes in the two groups over time. The effect of the group was significant (p < 0.001) and demonstrated that the Acu-TENS group had a higher SpO 2 level before the intervention compared to the control group (Figure 2).
It should be noted that the same changes were observed 4 days after the intervention (Figure 2).
Based on the results, for before and after the intervention difference, the effect of time was not significant (p = 0.488), indicating that there was no difference in increasing the SpO 2 between four days. Likewise, the time-group interaction was insignificant (p = 0.158) and indicated that SpO 2 changes over time for the two groups had similar changes. However, in the analysis, only the effect of the group was significant (p < 0.001) and implied that the Acu-TENS group had more increased SpO 2 in comparison to the control group (Figure 2).

| RR
Comparing the mean (SD) of RR in the first to fourth days before and after the intervention between Acu-TENS and control groups represented that there was no significant difference between the mean RR before and after the intervention between Acu-TENS and control groups in the first to fourth days (p > 0.05, Table 2).

| HR
Based on the mean and SD HR comparison between Acu-TENS and control groups in the first to fourth days before and after the T A B L E 1 Demographic characteristics of COVID-19 patients in the Acu-TENS and control groups.

| Severity of dyspnea
Comparing the mean and SD of the score of dyspnea between Acu-TENS and control groups in the first to fourth days before and after the intervention showed that the intervention did not affect the severity of dyspnea in patients (p > 0.05, Table 3). Table 4  In the current study, the RR of patients before the intervention was in the normal range, and the intervention did not affect RR.

| The need for mechanical ventilation, and the disease outcome
However, in the control group, fluctuations in the number of breaths were observed more than in the Acu-TENS group. In contrast, in the study by Ngai et al., 14 RR in the intervention group was significantly reduced after 4 weeks (20 sessions of Acu-TENS intervention).
Longer intervention time and longer follow-up (4 weeks compared to 4 days in our study) could be the reason for this difference in the results. Although one of the critical components of controlling vital signs is checking the RR; changes in the RR are occasionally unrelated to disease conditions such as heart and lung diseases and are sometimes mismeasured. 25 Studying animal models, Verhoeven et al. 26 found that SpO 2 was a reliable indicator of the severity of lung involvement with viral infections, and an increase in SpO 2 could better demonstrate the process of lung recovery from pathological conditions. Therefore, pulse oximetry can be a good alternative instead of controlling the RR. 25 In the present study, the HR of patients before the intervention was almost normal, and the intervention did not affect this parameter. However, the results of the study by Jones and Ngai 27 showed that healthy individuals received one Acu-TENS intervention before exercise, and their HR faster returned to resting HR after exercise. It is noteworthy that in the mentioned study, healthy T A B L E 3 The severity of dyspnea in COVID-19 patients in the Acu-TENS and control. It is necessary to mention that the patients did not experience any improvement in dyspnea during the 4 days of the intervention, thus the severity of dyspnea changed from moderate to severe at the beginning of the intervention at the end of 4 days of intervention in both Acu-TENS and control groups. Likewise, Öncü and Zincir 19 concluded that Acu-TENS intervention does not affect dyspnea in patients with COPD in the acute exacerbation phase. However, previous studies on patients with COPD and asthma confirmed a reduction in the severity of dyspnea after Acu-TENS intervention. [15][16][17][18] It should be noted that the present study was performed on hospitalized patients who were in the acute phase of the disease, which is similar to the study by Öncü and Zincir. 19 Dyspnea is a mental feeling affected by conditions such as weakness, anemia, lack of sleep, fatigue, fear, and anxiety, 28 and physically healthy people may have experienced dyspnea. 29 Hence, conditions such as COVID-19, which is associated with high levels of death anxiety 11 and respiratory muscle weakness, 30 may cause dyspnea in these patients even without being associated with the worsening of the patient's respiratory conditions. In a study by Leander et al., 31  Patients with COVID-19 who require intubation and mechanical ventilation due to complications of mechanical ventilation, including atelectasis, respiratory muscle paralysis, and lung dysfunction, have a worse prognosis in comparison to patients without the need for mechanical ventilation. 32 In this regard, in a study conducted in Iran, the mortality rate of people admitted to the ICU due to COVID-19 was reported to be 55.6%, which is more than other patients. 28 One of the leading causes of death in patients with COVID-19 is lung dysfunction because activated defense mechanisms and the fight against the virus cause lung damage and dysfunction. 29 In this disease, cytokine storm causes conditions such as acute respiratory distress syndrome and failure in many organs, thus adjusting these conditions is a necessary treatment and rescues these patients. 11 Traditional Chinese medicine, especially acupuncture, seeks to balance the yin and yang, thus eliminating factors that upset the balance of the body environment due to pathological conditions. 30 In general, the mechanism of action of Acu-TENS is still unknown. However, its effectiveness is probably due to stimulating endorphin secretion and inducing a decrease in airway resistance, resulting in easier breathing and inhibiting inflammatory cell release. 17

| Implications for practice
The most critical tasks of healthcare providers include evaluating the patient's respiratory condition, quickly identifying dyspnea, and performing an intervention to relieve an anxious feeling even in mild amounts. 33 Based on the present study's findings, Acu-TENS improved SpO 2 and patients' survival and decreased mechanical ventilation. Accordingly, this method can be used as one of the effective interventions to improve the respiratory outcome of COVID-19 during the pandemic since it is noninvasive and low-cost and can be performed by trained healthcare providers.

| Strength and limitations
One of the strengths of this research is its design as a randomized clinical trial, which is considered a gold standard for evaluating the effectiveness of the intervention.

| Conclusion
The Acu-TENS could improve SpO 2 as a respiratory outcome of patients with COVID-19 with moderate pulmonary involvement.
Since the control of oxygen saturation is an essential element in the management of COVID-19 patients and hypoxemia can lead to many acute adverse effects on their organ systems; the Acu-TENS can be used as one of the interventions to improve the respiratory outcome of the disease. participants. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CONFLICTS OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
All authors have read and approved the final version of the manuscript, and Mahboobeh Khajeh had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. Thus, the data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENTS
The authors acknowledge that the article has not been published

TRANSPARENCY STATEMENT
The lead author Mahboobeh Khajeh affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.